The over-arching goal of this P20 application is to develop a translational research center for the study of the neurobiology of cannabis dependence. The overall hypothesis under test is that dysregulation of frontal cortex function by cannabis impairs executive cognitive function thereby increasing vulnerability to cannabis dependence. Operationally, executive function is defined center-wide as mental control, initiative and fluency, self-monitoring, working memory and attention. Executive functioning will be characterized across species including rodents, non-human primates and humans, and across developmental stages from adolescence to adulthood. The Center is organized with four scientific Components and one Administrative and Scientific Core. The four scientific Components will evaluate: 1) the severity of brain and behavioral abnormalities associated with varying degrees of cannabis dependence in human adults (neuropsychological testing, fMRI, neurochemistry);2) brain and behavioral abnormalities associated with chronic cannabis use in human adolescents (neurochemistry, cognitive functioning, fMRI);3) brain and behavioral functional correlates of longitudinal exocannabinoid exposure in periadolescent monkeys (cognitive testing, chronophysiology, neurochemistry, fMRI);4) cannabinoid-induced alterations in neurotransmitter functions that underlie cortical dysfunction that may contribute to loss of executive functioning as evaluated in periadolescent and adult rodents (in vivo neurochemistry, behavioral pharmacology). Core scientific support functions include integrated subject recruitment and screening (Components 1 and 2), centralized specimen and tissue assessment (Components 1, 2, 3, and 4), CANTAB and fMRI task administration (Components 1, 2, and 3), and statistical consultation (Components 1, 2, 3, and 4). Core administrative functions will facilitate communication across components through regular meetings for Principal Investigators and trainees, in addition to posting of project details, progress reports, and abstracts on a dedicated website. Emphasis will be on top-down bottom-up communication and cross fertilization between components to predict the neurobiological, neurochemical and neuropsychological antecedents to this widespread and poorly understood disorder. Results will provide a heuristic framework for developing novel approaches to prevention, diagnosis and treatment of cannabis dependence.